RTF2 (replication termination factor 2) is a nuclear replisome component that plays dual roles in DNA replication stress response and viral restriction. Mechanistically, RTF2 associates with stalled replication forks and must be removed by proteasomal shuttle proteins DDI1 and DDI2 to enable optimal fork restart 1. Persistence of RTF2 at stalled forks impairs restart, leading to hyperactivated DNA damage signaling, ssDNA accumulation, and chromosome 20 1. RTF2 is also required for correct mRNA splicing of replication fork barrier proteins, potentially through interactions with splicing machinery 2. Beyond DNA replication, RTF2 functions as a nuclear-localized interferon-induced restriction factor that inhibits influenza virus primary transcription and promotes antiviral effector expression, with RTF2 loss enhancing viral replication 3. This protein is essential for cellular responses to replication stress agents like hydroxyurea 4. RTF2's clinical significance derives from its roles in maintaining genome integrity under replication stress—a hallmark of cancer and aging—and in innate antiviral immunity. Understanding RTF2 regulation may inform therapeutic strategies for replication stress-related diseases and viral infections.